There has been a significant and sustained growth in new drug production featuring monoclonal antibodies and other proteins, approximately 15-20% annually. This growth is due to expanding drug pipelines, as well as more efficient cell lines and bioreactor growth optimizations. The annual bio-production costs are currently estimated at $2.6 billion. One of the most significant investments a drug manufacturer has to make is process chromatography (approximately 30% or $850 million annually).
The industry has started to recognize that the efficiency of the chromatography steps which are used to purify the product proteins are no longer keeping up with production demands. There are a number of reasons for this.
First, no significant improvements have been made to the column chromatography process in the past 30 years—most of the work in the industry has been focused on new resin development. A notable exception is membrane chromatography which was recently adopted by the industry.
Second, upstream technology has improved tremendously in the same time period—the bioreactors are larger (up to 20,000 liters), and the titers are much higher (up to 15 g/L compared with 1-2 g/L five years ago). As a result of longer fermentation times, there are generally more impurities in the bioreactor effluent solution. All of the above reasons result in a much heavier load for the downstream purification.
Third, column chromatography has inherent physical limitations. Columns larger than 2 meter in diameter do not scale up. The largest columns in the market are 2 meter diameter and 40 cm bed height. They fit 1,250 L of resin. Assuming a binding capacity of 30 g/L of resin (common Protein A resin capacity for monoclonal antibodies), a single cycle can bind 38 kg. A 20,000 L bioreactor with an output of 10 g/L would produce a load of 200 kg. This means that the biggest column in the market would have to run at least 6 full cycles to process a single batch. The operation can take up to 24 hours and can result in a significant bottleneck for the manufacturing process.
Finally, in the present marketplace, disposability in the manufacturing process is gaining popularity. Disposable process steps save labor, do not require cleaning validation, and are easier to run for the manufacturing personnel. Strides have been made in most downstream processes to have disposable systems. These are—bioreactors (up to 2,000 L volume from Xcellerex Corp.), microfiltration (KleenPak TFF technology from Pall Corp.), depth filtration (POD Corp., Millipore Corp.), sterile filtration (all major manufacturers), tangential flow filtration (all major manufacturers), and membrane chromatography (Mustang, Pall Corp., Sartobind, and Sartorius Corp.). The column chromatography technology, because of its inherent limitations, cannot be a part of the disposable trend. Therefore, it is currently impossible to have a completely disposable downstream process—a purification train must include a chromatography step which cannot be disposable.
Therefore, it was recognized by the present inventor that a breakthrough in the state of the art would include solutions to the above problems. It was recognized that the industry needs 1) larger scale of operation; 2) faster processing time; 3) disposability; 4) reduction of media/resin expenses; and 5) a reduction of capital equipment investment.
It is against this background that various embodiments of the present invention were developed.